Ketotifen (Zaditen®, Zaditor®, Sandoz, Novartis) is a Generation-1 antihistamine that is mainly used for the treatment of allergic rhinitis. Ketotifen may be the most sedating of all marketed antihistamines, and the unusually severe sedative side effects of ketotifen have limited the therapeutic usefulness of the drug. In the USA, ketotifen is only used as eye drops (Zaditor®, Novartis) to alleviate the symptoms of allergic conjunctivitis in humans, and does not cause sedation due to the extremely low systemic concentrations of the drug after local administration to the eyes.
Other anti-inflammatory H-1 antihistamines are, for example, azatadine (Zadine®, Schering-Plough), chloropheniramine (Qdall®, Atley Pharmaceuticals), mepyramine (Pyrilamine®, Rhone-Poulenc, Tocris) and promethazine (Phenergan®, Baxter). All have antihistaminic (H-1) activity and all cause sedation and drowsiness.
Norketotifen (synonymously called RS-norketotifen), a hepatic metabolite of ketotifen, is an achiral molecule, but has two atropisomers, S-norketotifen and R-norketotifen, as has previously been described in U.S. Pat. Nos. 7,226,934 and 7,557,128. As explained in U.S. Pat. Nos. 7,226,934 and 7,557,128, norketotifen also had a significant sedation effect when studied in the art-accepted, and carefully validated mouse model of sedation, and further, the sedative effects were attributed to the R-isomer. It was thus proposed that only the S-isomer could be administered without sedative side effects.
Atopic dermatitis (AD) is a chronic allergic skin disease that occurs in 10 to 20 percent of children and 1 to 3 percent of adults. Of all patients suffering from AD, 40 to 60 percent also have respiratory allergies. Psoriasis is a chronic autoimmune dermal disease, caused by overproduction of new skin cells. Approximately 2.2 percent of the U.S. population suffers from psoriasis. Like patients with AD, psoriasis patients suffer from pruritus. Compromised skin barrier function has a role both in AD and psoriasis.
Many fungi have been described as normally living on the skin of various mammal species, including humans. Malassezia species form a family of lipolytic fungi that currently is believed to include 14 species. Overgrowth of Malassezia species causes toxic and/or immunological reactions and contributes to both AD and psoriasis, and also contributes to various other dermal diseases and conditions, such as for example, adult seborrheic dermatitis, dandruff, Malassezia folliculitis, tinea versicolor and rosacea. These fungal disorders are typically treated with medication for the underlying condition in combination with an antifungal mediation that can be administered orally or topically (dermally) to the skin.
Dermal bacterial infections are common in patients suffering from many dermal diseases, such as for example atopic dermatitis and psoriasis. These infections are often causative, as allergic reactions with inflammation and pruritus may be triggered by for example Staphylococcus aureus. As pointed out by Breuer et al., Allergy 2001, 56: 1034-1041, (2001), the skin of about 80 to 100 percent of patients with atopic dermatitis is colonized with Staphylococcus aureus, while Staphylococcus aureus can be found on the skin of only 5 to 30 percent of normal individuals. Breuer et al. (2001) and others have noted that the density of Staphylococcus aureus is increased according to the disease severity and that Staphylococcus aureus is causative for atopic dermatitis, since this bacterium promotes inflammation due to the action of superantigens. It was found by Brockow et al., Dermatology 1999, 199: 231-236 (1991) that topical antibacterial therapy in combination with an anti-inflammatory steroid not only reduced Staphylococcus aureus, but also reduced the severity of atopic dermatitis.
What is needed are methods of treating inflammatory dermal disorders without causing sedation or the much feared side effects of corticosteroids and immunosuppressant drugs. Also needed are improved topical treatments for combined inflammatory and infectious dermal disorders. Both topical and oral anti-pruritic medications are also needed.